5air

Structural highlights

Disease

LRP6_HUMAN Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis. The disease is caused by mutations affecting the gene represented in this entry.

Function

LRP6_HUMAN Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]} GSK3B_MOUSE Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-679' upon T-cell activation. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation.^{[11] [12] [13] [14] [15] [16] [17] [18]}

References

1. ↑ Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001 Jun 26;11(12):951-61. PMID:11448771
2. ↑ Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 2001 May 17;411(6835):321-5. PMID:11357136 doi:10.1038/35077108
3. ↑ Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005 May 20;280(20):19883-7. Epub 2005 Mar 18. PMID:15778503 doi:10.1074/jbc.M413274200
4. ↑ Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005 Dec 8;438(7069):873-7. PMID:16341017 doi:10.1038/nature04185
5. ↑ Swiatek W, Kang H, Garcia BA, Shabanowitz J, Coombs GS, Hunt DF, Virshup DM. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem. 2006 May 5;281(18):12233-41. Epub 2006 Mar 2. PMID:16513652 doi:10.1074/jbc.M510580200
6. ↑ Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J Biol Chem. 2007 May 25;282(21):15903-11. Epub 2007 Mar 30. PMID:17400545 doi:10.1074/jbc.M701927200
7. ↑ Mi K, Johnson GV. Regulated proteolytic processing of LRP6 results in release of its intracellular domain. J Neurochem. 2007 Apr;101(2):517-29. Epub 2007 Feb 26. PMID:17326769 doi:10.1111/j.1471-4159.2007.04447.x
8. ↑ Piao S, Lee SH, Kim H, Yum S, Stamos JL, Xu Y, Lee SJ, Lee J, Oh S, Han JK, Park BJ, Weis WI, Ha NC. Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS One. 2008;3(12):e4046. doi: 10.1371/journal.pone.0004046. Epub 2008 Dec 24. PMID:19107203 doi:10.1371/journal.pone.0004046
9. ↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
10. ↑ Wu G, Huang H, Garcia Abreu J, He X. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One. 2009;4(3):e4926. doi: 10.1371/journal.pone.0004926. Epub 2009 Mar 18. PMID:19293931 doi:10.1371/journal.pone.0004926
11. ↑ Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000 Jul 6;406(6791):86-90. PMID:10894547 doi:http://dx.doi.org/10.1038/35017574
12. ↑ McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 2005 Apr 20;24(8):1571-83. Epub 2005 Mar 24. PMID:15791206 doi:http://dx.doi.org/10.1038/sj.emboj.7600633
13. ↑ Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006 Mar 17;21(6):749-60. PMID:16543145 doi:http://dx.doi.org/10.1016/j.molcel.2006.02.009
14. ↑ Garrido JJ, Simon D, Varea O, Wandosell F. GSK3 alpha and GSK3 beta are necessary for axon formation. FEBS Lett. 2007 Apr 17;581(8):1579-86. Epub 2007 Mar 19. PMID:17391670 doi:http://dx.doi.org/10.1016/j.febslet.2007.03.018
15. ↑ Tanabe K, Liu Z, Patel S, Doble BW, Li L, Cras-Meneur C, Martinez SC, Welling CM, White MF, Bernal-Mizrachi E, Woodgett JR, Permutt MA. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 2008 Feb;6(2):e37. doi: 10.1371/journal.pbio.0060037. PMID:18288891 doi:http://dx.doi.org/10.1371/journal.pbio.0060037
16. ↑ Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y. DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol. 2010 Apr;30(7):1757-68. doi: 10.1128/MCB.01047-09. Epub 2010 Feb, 1. PMID:20123978 doi:http://dx.doi.org/10.1128/MCB.01047-09
17. ↑ Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E. Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta. Cell. 2011 Feb 4;144(3):341-52. doi: 10.1016/j.cell.2010.12.033. PMID:21295697 doi:http://dx.doi.org/10.1016/j.cell.2010.12.033
18. ↑ Wakatsuki S, Saitoh F, Araki T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol. 2011 Nov 6;13(12):1415-23. doi: 10.1038/ncb2373. PMID:22057101 doi:http://dx.doi.org/10.1038/ncb2373